Reveliza^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Generium-Next, LLC (Russia)

Manufactured By

Generium, JSC (Russia)

Or

PK-137, LLC (Russia)

Labeled By

PK-137, LLC (Russia)

Or

Generium, JSC (Russia)

Packaging and Quality Control Release

Generium-Next, LLC (Russia)

Quality Control Release

Generium, JSC (Russia)

ATC Code

B01AD02 (Alteplase)

Active Substance

Alteplase (Rec.INN registered by WHO)

Dosage Form

Reveliza®

Lyophilizate for preparation of solution for infusion 50 mg: vial in set with solvent

Dosage Form, Packaging, and Composition

Lyophilizate for preparation of solution for infusion in the form of an amorphous mass from white to white with a slightly yellowish tint; solvent is a colorless transparent liquid without odor.

1 ml of the reconstituted solution contains 1 mg of alteplase (rt-PA).

Excipients: arginine, polysorbate 80, phosphoric acid.

Solvent water for injections – 50 ml.

Vials (1) in a set with solvent (vial 50 ml 1 pc.) – cardboard packs with a divider.

For first opening control, the package valves are fixed with self-adhesive labels.

Clinical-Pharmacological Group

Thrombolytic – tissue plasminogen activator

Pharmacotherapeutic Group

Antithrombotic agents; enzymes

Pharmacological Action

Thrombolytic agent. It remains inactive in the bloodstream until it binds to fibrin, to which it has a high affinity; after which it stimulates the conversion of fibrin-bound plasminogen into active plasmin.

It acts directly on the fibrin clot and promotes its dissolution. The effect on the components of the blood fibrinolytic system is insignificant. It has low antigenic activity.

Pharmacokinetics

After bolus administration, the concentration of the active substance in plasma from the initial level is 50% after 5 min; 20% – after 10 min; less than 10% – after 20 min.

Alteplase is rapidly eliminated from the circulating blood and is metabolized mainly in the liver.

Indications

Thrombolytic therapy of acute myocardial infarction (within the first 6-12 hours from the onset of the disease).

Thrombolytic therapy of ischemic stroke in the acute period (after exclusion of intracranial bleeding).

Thrombolytic therapy of acute thromboembolism (including pulmonary embolism).

ICD codes

Dosage Regimen

Administer the dosage regimen individually, based on the specific clinical indication and patient weight.

For acute myocardial infarction, administer a total dose of 100 mg as a 90-minute infusion. Initiate with a 15 mg IV bolus. Follow with an infusion of 50 mg over 30 minutes. Then administer the remaining 35 mg over 60 minutes.

For acute massive pulmonary embolism, administer a total dose of 100 mg as a 2-hour infusion. Administer 10 mg as an IV bolus over 1-2 minutes. Follow with a continuous infusion of 90 mg over the remaining 2 hours.

For acute ischemic stroke, administer a total dose of 0.9 mg/kg (maximum 90 mg) as a 60-minute infusion. Initiate with a bolus of 10% of the total dose administered intravenously over 1 minute. Infuse the remaining 90% of the dose over the subsequent 60 minutes.

Do not exceed the maximum total dose of 100 mg for myocardial infarction or pulmonary embolism, or 90 mg for acute ischemic stroke.

Initiate treatment for acute ischemic stroke within 4.5 hours of symptom onset. Carefully assess the benefit-risk ratio in patients over 80 years of age due to an increased risk of intracranial hemorrhage.

Reconstitute the lyophilizate strictly according to the manufacturer’s instructions using the provided sterile water for injections. Do not mix with other medicinal products in the same infusion solution. Inspect the reconstituted solution visually for particulate matter and discoloration prior to administration; discard if present.

Adverse Reactions

From the hematopoietic system bleeding limited to the injection site is possible (is not a reason to discontinue treatment).

The risk of hemorrhagic complications increases when using a dose of 100 mg or more (in isolated cases – intracranial hemorrhages).

From the cardiovascular system cardiac arrhythmias (myocardial reperfusion syndrome), local cholesterol crystal embolism or microthromboembolism.

Contraindications

Hypersensitivity to alteplase, age over 80 years, therapy of acute stroke in children and adolescents under 18 years of age.

Should not be used in the presence of an increased risk of bleeding: extensive bleeding at present or within the previous 6 months; hemorrhagic diathesis; simultaneous effective treatment with oral anticoagulants, for example, warfarin (INR >1.3); history of CNS diseases (including neoplasms, aneurysm, surgical intervention on the brain or spinal cord); intracranial (including subarachnoid) hemorrhage at present or in history; suspicion of hemorrhagic stroke; severe uncontrolled arterial hypertension; extensive surgical intervention or severe trauma within the previous 10 days (including any trauma received against the background of developing myocardial infarction); recently suffered traumatic brain injury; prolonged or traumatic cardiopulmonary resuscitation (more than 2 min); childbirth within the previous 10 days; recently performed puncture of non-compressible blood vessels (for example, subclavian or jugular vein); severe liver diseases, including hepatic failure, liver cirrhosis, portal hypertension (including with esophageal varices), active hepatitis; bacterial endocarditis, pericarditis; acute pancreatitis; confirmed gastric and duodenal ulcer within the last 3 months; arterial aneurysms, malformations of arteries and veins; neoplasms with an increased risk of bleeding; hypersensitivity to alteplase.

Additional contraindications in case of use for the treatment of acute myocardial infarction and pulmonary embolism: history of hemorrhagic stroke or stroke of unknown etiology; ischemic stroke or transient ischemic attacks within the last 6 months (except for the current acute ischemic stroke within 4.5 hours).

Additional contraindications in case of use for the treatment of acute ischemic stroke: onset of ischemic stroke symptoms more than 4.5 hours before the start of infusion, or lack of accurate information about the time of onset of the disease; rapid improvement in condition with acute ischemic stroke or mild severity of symptoms at the time of infusion; severe stroke, based on clinical data (for example, if the NIHSS (National Institutes of Health Stroke Scale) score >25) and/or according to the results of appropriate imaging methods (CT or MRI); seizures at the onset of stroke; information about a previous stroke or serious head injury within the previous 3 months; occurrence of a previous stroke against the background of diabetes mellitus; use of heparin within 48 hours before the onset of stroke, if at this time the APTT is increased; platelet count <100,000/µl; systolic BP above 185 mm Hg or diastolic BP above 110 mm Hg or the need for intensive therapy (IV administration of drugs) to reduce BP to these limits; blood glucose concentration <3 or >20 mmol/l.

Use in Pregnancy and Lactation

Clinical experience with the use of alteplase during pregnancy is limited.

In experimental studies it was shown that Alteplase does not penetrate the placental barrier in rats; no negative effect on the fetus was found.

Use in Hepatic Impairment

Contraindications: hepatic failure, liver cirrhosis, portal hypertension (with esophageal varices), active hepatitis.

Pediatric Use

Contraindication: therapy of acute stroke in children and adolescents under 18 years of age.

Geriatric Use

Contraindication: age over 80 years.

Special Precautions

In case of development of hemorrhagic complications, the administration of alteplase should be stopped, if possible, compression of the bleeding vessel should be applied; due to the short T_1/2 of alteplase, coagulation therapy is usually not required.

With caution, after assessing the degree of expected benefit and the possible risk of bleeding, it should be used for: recently performed IM injection or small recent interventions, such as biopsy (with a needle), puncture (with a needle) of large vessels, cardiac massage during resuscitation; diseases (not mentioned in the list of contraindications) in which the risk of bleeding is increased; with simultaneous use of oral anticoagulants, the use of alteplase can be considered only if the laboratory parameters of anticoagulant activity are not clinically significant.

When treating acute myocardial infarction and acute pulmonary embolism, the following special warnings and precautions should be additionally taken into account: systolic BP > 160 mm Hg; old age, which may increase the risk of intracranial hemorrhage. Since in elderly patients the likelihood of a positive outcome of this treatment also increases, a careful assessment of the benefit/risk ratio is necessary.

When treating acute ischemic stroke, the following special warnings and precautions should be additionally taken into account: use in patients with acute ischemic stroke, compared with use for other indications, is associated with an increased risk of intracranial hemorrhage, since bleeding occurs predominantly in the necrotic area.

This should be especially taken into account in the following cases: all conditions characterized by a high risk of bleeding; presence of small asymptomatic cerebral vascular aneurysms; delay in the start of treatment; in patients who were previously treated with acetylsalicylic acid or other antiplatelet agents, there may be an increased risk of intracerebral hemorrhage, especially if the use of alteplase is started at a later time. Given the increased risk of cerebral hemorrhage, the dose of alteplase used should not exceed 0.9 mg/kg (maximum dose is 90 mg). In patients over 80 years of age, compared with younger patients, the risk of cerebral hemorrhage may increase and the overall effectiveness of treatment may decrease, so the issue of using alteplase should be decided taking into account the expected risk.

Treatment should not be started later than 4.5 hours after the onset of symptoms, due to an unfavorable benefit/risk ratio, which is due to the following circumstances: the positive effect of treatment decreases with a late start of therapy; mortality increases mainly in patients who previously received acetylsalicylic acid; the risk of bleeding increases.

Drug Interactions

With simultaneous use of alteplase with indirect anticoagulants, antiplatelet agents, heparin and other drugs that reduce blood clotting, the risk of hemorrhagic complications increases.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.